It is known that interactions between tumor and endothelial cells have a significant influence on the growth and metastasis of malignant tumors.To study the reciprocal effect of Lewis lung carcinoma (LLC) and endothelial cells on the growth rate of each other upon their co-cultivation in vitro and to assess the contribution of such tumor/endothelial cell crosstalk to in vivo LLC growth and metastasis.Two variants of Lewis lung carcinoma cells, high-metastatic (LLC) and low-metastatic (LLC/R9), and murine aorta endothelial cell line (MAEC) were used. Kinetics of tumor cell growth in vitro and in vivo, electrokinetic properties of tumor cells and their adhesion to endothelial monolayer, and the number of tumor and endothelial viable cells after 1-day contact or non-contact co-cultivation were estimated.LLC/R9 had significantly higher growth rate in vivo (as opposed to in vitro) than LLC. However, the number and volume of lung metastatic lesions in LLC/R9-bearing mice were 4.5-fold (p < 0.05) and 3.6-fold lower (p < 0.05), respectively, compared to those in LLC-bearing mice. Non-contact co-cultivation of LLC/R9 + MAEC caused more than a 34% (p < 0.05) LLC/R9-induced increase in the number of MAEC and a 60% (p < 0.05) MAEC-induced increase in the number of LLC/R9 cells as compared to those of corresponding controls (cells cultured alone). In contrast, in the case of LLC + MAEC, both the number of LLC and MAEC cells after their non-contact co-cultivation and cultivation alone did not differ significantly. Contact co-cultivation LLC+MAEC (in contrast to LLC/R9+MAEC) caused more than a 50% (p < 0.01) LLC-induced decrease in the number of MAEC and a 50% decrease (p < 0.05) MAEC-induced in the number of LLC cells as compared to the corresponding controls. Both tumor cell variants showed a bimodal distribution of cells by ζ-potential, but in the case of LLC there was observed a shift towards high values due to 52% of cells with a surface charge density > 10 C/m2, while in the case of LLC/R9 such a subpopulation was absent and 19% of cells had a surface charge < 5 C/m2. The number of LLC cells that adhered to the monolayer of endothelial cells was by 65% (p < 0.05) higher than that of LLC/R9 cells.Obtained data demonstrated that the tumor/endothelial cell relationships might reflect the features of tumor growth and metastasis of a malignant tumor.
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Актуальність теми дослідження. Якість робочих поверхонь зубчастих коліс формується під впливом конструктивних факторів (модуля, числа зубців і матеріалу коліс, твердості матеріалу заготовок та їх фізикомеханічних властивостей) і технологічних факторів (швидкості та глибини різання, подачі, ступеня зношуваності інструменту). Зубчасту передачу можна виконати тільки з деяким наближенням до функціонально точної, оскільки елементи зубчастої передачі не можуть бути виготовлені без відхилень. Рівень цих відхилень визначається не тільки технічною, але й економічною доцільністю, а також можливостями виробництва. Постановка проблеми. Виявлення можливості збільшення ресурсів зубчастих передач, зокрема головного, проміжного і хвостового редукторів вертольотів Ми-8 та їх модифікацій. Аналіз останніх досліджень і публікацій. З аналізу літературних джерел можна зробити висновок, що основними факторами, що формують якість робочих поверхонь зубчастих коліс, є конструктивні та технологічні. Сучасні досягнення у сфері конструювання та виробництва сприяють підвищенню точності та зменшенню погрішностей зубчастих передач вертольотних редукторів. Виділення недосліджених частин загальної проблеми. Виявити основні причини виникнення погрішностей зубчастих передач вертольотних редукторів, взаємозв’язок факторів виробництва й параметрів точності зубчастих коліс та можливості керування точністю поверхонь зубців ще на стадії проєктування. Мета статті. Розглянути точність та погрішності зубчастих передач вертольотних редукторів. Виклад основного матеріалу. Розглянуті показники точності зубчастих коліс за нормами кінематичної точності, плавності, контакту зубців та бокового зазору, вплив технології виробництва на якість зубчастих коліс. Функціональна точність забезпечується двома шляхами – конструктивним і технологічним. Приведені основні причини виникнення погрішності операції зубофрезерування, можливості керування точністю та якістю поверхонь зубців ще на стадії проєктування, взаємозв’язок факторів виробництва й параметрів точності зубчастих коліс. Наведені приклади кінематограм показують неприйнятність кінематичного принципу нормування і контролю точності напружених зубчастих передач та передач з модифікованими поверхнями зубців. Тому нормування та оцінювання точності авіаційних зубчастих коліс здійснюють виключно за елементними показниками точності. Показано, що колеса необхідно контролювати по накопиченій погрішності кроку, а не по биттю. Розглянуто контроль за допомогою плям контакту для конічних передач із прямими і круговими зубцями. Висновок відповідно до статті. Збільшення ресурсу передач здійснюється, поза іншими способами, підвищенням точності виготовлення зубчастих коліс, яка у високоресурсних і високонапружених передачах досягає 4-го ступеня точності за нормами плавності та контакту. У багатьох випадках подальше підвищення точності при збільшенні ресурсу не є доцільним, оскільки висока навантаженість коліс на всіх режимах роботи забезпечує статичний розподіл навантаження між спряженими зубцями, що призводить до зменшення динамічного зусилля. Тут прослідковується основний принцип призначення точності авіаційних передач: точність призначається з урахуванням фактичної навантаженості та жорсткості спряжених зубців і всієї пружної системи загалом.
The ability to metabolic reprogramming is a distinctive feature of metastatically active tumor cells. A classic example of metabolic reprogramming, characteristic of almost all malignant cells, is aerobic glycolysis. Therefore, inhibition of glycolysis in tumor cells is considered a promising strategy for antitumor therapy.
Today, the ability for metabolic reprogramming is considered one of the distinguishing features of metastatically active tumor cells, a classic example of which is aerobic glycolysis. Despite a large number of studies in this direction, the question of the relationship between the intensity of aerobic glycolysis and the metastatic potential of tumor cells remains almost completely open. The work aimed to investigate the effect of the lactate dehydrogenase (LDH) inhibitor on the viability and several characteristics of Lewis lung carcinoma cells with different metastatic potential.High-metastatic (LLC) and low-metastatic (LLC/R9) variants of Lewis lung carcinoma cells were used. After 24 h of tumor cells incubation with or without 40 mM sodium oxamate, cell viability, the concentration of glucose and lactate in the incubation medium, distribution of cells by the cell cycle phases, and intracellular ROS production were estimated.It was revealed that regardless of the metastatic potential, LLC cells are heterogeneous in terms of both the involvement of aerobic glycolysis in their growth and survival processes and the sensitivity to the cytotoxic/cytostatic action of an LDH inhibitor. 35% of cells of either LLC variant form an oxamate-resistant subpopulation while 65% are oxamate-sensitive. The rate of glucose consumption of LLC/R9 cells in the absence of oxamate is almost twice higher compared to LLC and, as a result, the sensitivity of these cells to the cytotoxic/cytostatic effect of oxamate also is significantly higher (the IC50 for LLC/R9 cells is by 35.8% lower than that for LLC cells, p < 0.05). Approximately one-third of the cells of both LLC and LLC/R9 variants can survive and proliferate when aerobic glycolysis is completely inhibited by oxamate. This indicates metabolic reprogramming (either pre-existing or dynamically arising in response to inhibition of glycolysis) of this subpopulation of cells, within which not only the survival of cells but also their proliferative activity is most likely based on glutamine metabolism.Such metabolic heterogeneity of metastatically active cells indicates that inhibition of glycolysis as monotherapy is insufficient for effective antimetastatic therapy. Presumably, more effective would be to involve various inhibitors of metabolic processes that ensure the metabolic plasticity of metastatic cells.
Aerobic glycolysis that supports high proliferation rate and survival of tumor cells in unfavorable conditions is among fundamental features of tumor metabolism. The search for active modulators of energetic metabolism capable of suppressing tumor growth and metastasis could result in higher effectiveness of anticancer therapy. Aim: To study antitumor and antimetastatic activity of the modulators of energetic metabolism dichloroacetate (DCA) and 2-deoxy-D-glucose (2DG) used in combination treatment of Lewis lung carcinoma (LLC). Materials and Methods: As experimental tumor model, LLC/R9 variant was used. DCA and 2DG were administered per os to С57Bl/6 mice 5 times per week for 3 weeks at a total dose of 1.5 and 0.98 g/kg, respectively, as single agents or in combination starting from the following day after tumor cell transplantation. Growth of primary tumor and number and volume of lung metastases were registered. Lactate and pyruvate content was determined by enzymatic methods using lactate dehydrogenase. Electron paramagnetic resonance was used for analyzing the functional state of the components of mitochondrial respiratory chain. Engulfing activity and reactive oxygen species (ROS) production in tumor-associated CD14+ cells was analyzed by flow cytometer with the use of FITC-labeled staphylococcus, and by spectrofluorometry with the use of 2.7-dichlorofluorescein diacetate, respectively. Results: DCA administered as a single agent did not affect primary tumor growth but decreased the number and volume of lung metastases by 60% (p < 0.05) and 90% (p < 0.05), respectively. In mice treated with 2DG only, primary tumor volume as well as the number and volume of lung metastases were not affected. Combination treatment with DCA and 2DG resulted in the decrease of primary tumor volume, the number and volumes of lung metastases by 70; 46, and 90%, respectively (р < 0.05). High antitumor activity of DCA + 2DG was associated with 31% decrease (p < 0.05) of lactate content in tumor tissue and 120% increase (p < 0.01) of ROS production in СD14+ cells recruited to the region of tumor growth. Conclusion: 2DG that possesses neither antitumor nor antimetastatic activity against LLC/R9 significantly enhanced antitumor activity of DCA with accompanying inhibition of glycolysis and increase of cytotoxic activity of CD14+ cells infiltrating tumor tissue. Taking into account significant antimetastatic activity of DCA this substance could be considered as a promising antimetastatic agent.
Summary. Background: Taking into account differences in the bioenergetics between malignant and normal cells a search of antitumor drugs among the modifiers of tumor metabolism has a reasonable excuse. Earlier it was found that the cytotoxic/cytostatic action of sodium dichloroacetate (DCA) against Lewis lung carcinoma (LLC) cells in vitro was enhanced in the case of its combination with metformin (MTF). Aim: To study the antitumor action of DCA in combination with MTF against LLC in vivo. Materials and Methods: LLC/R9, a low metastatic variant of LLC cells, was used. LLC/R9 bearing mice were treated with MTF (at a total dose 0.15 g/kg b.w.) alone or in combination with DCA (at a total dose of 0.75 g/kg b.w.). LLC/R9 growth kinetics and the primary tumor growth and metastasis indices on the 23rd day after tumor cell inoculation were evaluated by routine procedures. The state of the electron transport chain of mitochondria in tumor cells was studied using electron paramagnetic resonance. The content of lactate and glucose in blood plasma from mice was measured by enzymatic methods using biochemical analyzer. The number of tumor-associated macrophages (TAMs) and their distribution by M1/M2 phenotype were estimated by flow cytometry using antibodies against CD68 and CD206. Results: In LLC/R9-bearing mice treated with DCA in combination with MTF, tumor growth and metastasis indices, as well as circulating glucose and lactate levels were not significantly different from those in the control group. The level of nitrosylation of non-heme and heme proteins and the content of iron-sulfur centers in the mitochondria of tumor cells in LLC/R9-bearing mice administered with DCA in combination with MTF did not also differ from the corresponding indices in control. Instead, in tumors treated with MTF alone and in combination with DCA the total CD68+ TAMs count was almost 27% (p < 0.05) and 43% lower (p < 0.05) correspondingly than that in control, but this decrease was not accompanied by redistribution of CD68+/CD206+ and CD68+/D206- subsets. Conclusion: DCA in combination with MTF, at least in doses applied, did not affect LLC/R9 growth and metastasis in vivo. The complete absence of an antitumor effect of DCA in combination with MTF was simultaneously associated with the absence of significant changes in the functional state of electron transport chain of mitochondria in tumor cells, circulating glucose and lactate levels, and the decrease of the TAMs amount in tumors. It suggests that the antitumor activity of DCA and MTF could be determined by both their local effects within a tumor and their multiple systemic impacts.
To analyze the growth kinetics and proliferative heterogeneity of Lewis lung carcinoma (LLC) cells during their growth in monolayer for 5 days without replacement of culture medium (unfed culture).Cell biology methods, sandwich enzyme-linked immunosorbent assay for vascular endothelial growth factor (VEGF) detection (ELISA), enzymatic glucose-oxidase method for glucose measurements, mathematical modeling.Created mathematical model showed good fit to experimental data; that allowed to determine kinetic (model) parameters of LLC cells and predict the changes in number of proliferating and quiescent cells (proliferative heterogeneity) during their growth. It was shown that growth kinetics of viable LLC cells possesses non-monotonous character - during first three days of growth the number of cells raised exponentially, with following decrease after the maximal level was achieved. At the same time the decrease of number of viable cells/increase of number of dead cells has been observed upon complete depletion of culture medium by glucose content. Glucose dependence of cell transition rate from proliferation to resting state predicted by mathematical model possessed a pronounced two-phase character. At a wide range of relatively high glucose concentrations (> 1.0 mg/ml) the transition rate was close to zero. At concentrations lower than 0.7 mg/ml, the rate of transition swiftly increased resulting in sharp change in cellular composition. At an interval from 70 to 90 h, practically all proliferating cells transited to a resting state. The rate of quiescent cell death was relatively low, and this was in part caused by too low level of glucose consumption compared to proliferating cells. It was shown that during LLC cells growth VEGF production rate decreased monotonously in spite of the fact that the level of VEGF in incubation medium increased monotonously. Observed monotonous decrease of VEGF production rate could not be explained by VEGF degradation in incubation medium (our results displayed the stability of VEGF molecule during investigations).Weak dependence of cell transition rate from proliferating to resting state from glucose level (> 0.7 mg/ml) and low rate of cell death provided slow decrease of the pool of quiescent cells in the population, thus significantly increasing their chance to survive upon nutritional deficiency.
The majority of tumor-associated macrophages exhibit the M2 phenotype, which is an important determinant of tumor development and metastasis. Reducing the number of intratumoral M2 macrophages is an urgent task. It has been revealed that blockade of glycolysis by sodium oxamate or the glutamine-free medium both suppresses the ability of high-metastatic (LLC) and low-metastatic (LLCR9) Lewis lung carcinoma cells to macrophage reprogramming into the M2 phenotype.
Correction for ‘Bioactivity of cerium dioxide nanoparticles as a function of size and surface features’ by Veronika Sarnatskaya et al. , Biomater. Sci. , 2024, 12 , 2689–2704, https://doi.org/10.1039/D3BM01900D.
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